ArticleJournal of the National Cancer Institute2022
A Novel Locus on 6p21.2 for Cancer Treatment-Induced Cardiac Dysfunction Among Childhood Cancer Survivors.
Article in Journal of the National Cancer Institute, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 4 of them syntheses that pooled it.
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Who cites it
9 citing papers in PubMed, 4 syntheses or guidelines pooled it, 12 citations in OpenAlex.
- Influence of genetic biomarkers on cardiac diseases in childhood cancer survivors: a systematic review.The pharmacogenomics journal · 2025Pooled it
- Clinical and cost-effectiveness of pharmacogenomic testing for anthracycline-induced cardiotoxicity in childhood cancer: a systematic review and meta-analysis.Frontiers in pharmacology · 2025Pooled it
- Genetic susceptibility to cognitive decline following craniospinal irradiation for pediatric central nervous system tumors.Neuro-oncology · 2023Pooled it
- Pharmacogenetics of chemotherapy treatment response and -toxicities in patients with osteosarcoma: a systematic review.BMC cancer · 2022Pooled it
- Cardiac Manifestations ofHealth science reports · 2026Review
- Predicting the 10-year risk of cardiomyopathy in long-term survivors of childhood cancer.Annals of oncology : official journal of the European Society for Medical Oncology · 2025Article
- Genetic and epigenetic bases of long-term adverse effects of childhood cancer therapy.Nature reviews. Cancer · 2025Review
- Improved Cardiomyopathy Risk Prediction Using Global Longitudinal Strain and N-Terminal-Pro-B-Type Natriuretic Peptide in Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2024Article
- Uncovering the Genetic Etiology of the (Posttherapy) Broken Heart.Journal of the National Cancer Institute · 2022Article
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28 authors at 9 institutions in 2 countries.
Funding
Abstract
backgroundAdult survivors of childhood cancer are at increased risk of cardiac late effects.
methodsUsing whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided.
resultsA variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors.
conclusionsLeveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association.
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